Hippocampal sharp-wave ripple and replay mechanisms underlying long-term memory

项目总结 哺乳动物的大脑具有非凡的存储和检索记忆的能力。特别是，突出的事件 所谓的尖波纹波(SWR)与海马体中记忆的巩固和回忆有关。 这些事件是由两个海马区的同步去极化引起的高频振荡 大脑半球，它们发生在清醒的休息或睡眠中。在SWR期间，被激活的神经系综 在清醒过程中，体验以短时间的压缩序列在休息时重新激活，这一过程称为 “重播”。由于它们的大规模性质，尖锐的波纹和重播事件可能会形成 海马区内的可塑性促进记忆。研究表明，延长持续时间 在24小时内完成的空间任务中，SWR可以改善记忆，而干扰SWR则会 在这些空间任务中会损害记忆。尽管SWR可以在短时间内影响记忆过程，但它们 在长时间尺度上保存记忆的作用在很大程度上仍不清楚。这项提案将探索 SWRs通过产生形成和维持可塑性来增强长期记忆稳定性的假说 合唱团。 我们将研究SWRs如何塑造在海马区CA1区编码的空间记忆的稳定性 在虚拟现实环境中导航。这项研究将解决两个目标。在目标1中，我们将衡量这些影响 SWR影响了整个人口的地点代码的稳定性，并在几周内重播事件。建议数 实验将利用体内双光子钙成像和电生理记录来评估 SWR是否会在几周内在人口水平上产生稳定的总体。在目标2中，我们将 确定SWR和重播事件如何塑造重播合奏中的微电路组织。这些 实验将利用高速双光子光遗传刺激方法来光学测量原因 重放系综内单元之间的功能连通性以及确定SWR是否可以生成 可塑性将细胞招募到重播组合中。我们假设主权财富基金有助于建立 时间稳定的记忆痕迹，通过加强重播合奏中的因果功能联系。 这些结果将为稳定Long的记忆集合的神经机制提供洞察力 时间尺度，这对于理解长时记忆过程是如何实现的至关重要。长期的 患有记忆障碍和阿尔茨海默病、痴呆症、 和健忘症，所以这项提议的发现将有助于为理解糖尿病的病理基础 这些情况并将有助于为这些患者开发新的治疗方法。

Project summary The mammalian brain has the remarkable capacity to store and retrieve memories. In particular, salient events called sharp-wave ripples (SWRs) are implicated in the consolidation and recall of memories in the hippocampus. These events are high frequency oscillations caused by synchronous depolarizations across both hippocampal hemispheres, and they occur during awake rest or sleep. During SWRs, neural ensembles that are activated during awake experiences are reactivated in rest in compressed sequences of short durations, a process called ‘replay’. Because of their large-scale nature, sharp-wave ripples and replay events can potentially shape plasticity within hippocampal ensembles to promote memory. Studies have shown that lengthening the duration of SWRs can improve memory on spatial tasks performed less than 24 hours later, while disrupting SWRs will impair memory on these spatial tasks. Though SWRs can influence memory processes on short timescales, their role in preserving memories across long timescales remains largely unknown. This proposal will explore the hypothesis that SWRs enhance the stability of long-term memories by generating plasticity to form and maintain ensembles. We will investigate how SWRs shape the stability of spatial memories encoded in hippocampal region CA1 during navigation in virtual reality environments. This study will address two aims. In Aim 1, we will measure the effects SWRs have on the stability of the population-wide place code and replay events across weeks. The proposed experiments will leverage in vivo two-photon calcium imaging and electrophysiological recordings to evaluate whether SWRs causally create stable ensembles on the population level across weeks. In Aim 2, we will determine how SWRs and replay events shape microcircuit organization within replay ensembles. These experiments will utilize a high-speed two-photon optogenetic stimulation approach to optically measure causal functional connectivity between cells within the replay ensemble and to determine whether SWRs can generate plasticity to recruit cells into the replay ensemble. We hypothesize that SWRs contribute to establishing temporally stable memory traces by strengthening the causal functional connections within replay ensembles. These results will provide insight on neural mechanisms that stabilize memory ensembles across long timescales, which is critical for understanding how long-term memory processes are implemented. Long-term memory is impaired in patients with memory disorders and conditions such as Alzheimer’s disease, dementia, and amnesia, so findings from this proposal will help provide a foundation for understanding the pathology of these conditions and will help in the development of new therapies for these patients.